Herpes simplex virus (HSV) can cause a wide range of diseases including skin lesions which are common, encephalitis which is rare, and HSV infection of the eye which is a leading cause of blindness in the USA. Herpes virus infections are characterized by the ability of the virus to become latent. It is this ability, which leads to recurrent episodes of disease, and which is the focus of this grant. The overall goal of this proposal is to understand the mechanism of HSV latency and reactivation using both a mouse model system and human autopsy tissue. We have previously used the mouse model system of HSV latency to study the physical state of the latent viral genome and to initiate studies on viral gene expression during latency. From our data, we have formulated some models for the mechanism of HSV-1 latency and reactivation. We now wish to explore, and refine, these models using the techniques of molecular virology. The program consists of three scientific projects and a scientific core. The scientific projects are titled: Gene Expression During HSV-1 Latency and Reactivation; The Role of Cellular Transcription Factors in the Regulation of HSV-1 Latency and Reactivation; Viral Genetics of Herpes Simplex Virus Latency. If these studies are successful, then the mechanism of HSV latency and reactivation will be described in sufficient detail to formulate strategies to prevent latency and recurrence.